2-(6&#39;-methoxy-2&#39;-naphthyl)propionic acid and -1-propanol derivatives having anti-inflammatory,analgesic and anti-pyretic activities

ABSTRACT

2-(6&#39;&#39;-METHOXY-2&#39;&#39;-NAPTHYL)-1-PROPYL 2&#34;-ACETOXYBENZOATE AND 2&#34;-CARBOXYPHENYL 2-(6&#39;&#39;-METHOXY - 2&#39;&#39; - NAPTHYL) PROPIONATE HAVE ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ACTIVITIES.

2-(6'-METHOXY-2'-NAPH'IHYL)PROPIONIC ACID AND -1-PROPANOL DERIVATIVES HAVING ANTI-INFLAMMATORY, ANALGESIC AND ANTI-PYRETIC ACTIVITIES John H. Fried and Ian T. Harrison, Palo Alto, Calif., assignors to Syntex Corporation, Panama No Drawing. Filed Jan. 11, 1971, Ser. No. 105,651 Int. Cl. A611: 27/00 US. Cl. 424-308 4 Claims ABSTRACT OF THE DISCLOSURE 2-(6'-methoxy-2'-naphthyl)-1-propyl 2"-acetoxybenzoate and 2"-carboxyphenyl 2-(6'-methoxy 2 naphthyl) propionate have anti-inflammatory, analgesic and antipyretic activities.

This invention relates to derivatives of 2-(6'-methoxy- 2'-naphthyl)propionic acid and 2-(6'-methoxy-2'-naphthyl)-1-propanol, compositions containing these derivatives, and methods for treating inflammation, pain and pyrexia therewith.

In summary, the compounds of this invention are 2(6'- methoxy-2'-naphthyl)-l-propyl 2-acetoxybenzoate and 2"-ca.rboxyphenyl 2-(6'-methoxy-2-naphthyl)propionate.

The compositions of this invention comprise one or both of the above compounds in combination with one or more pharmaceutically acceptable excipients. The above compounds can be orally administered for the treatment and elimination of inflammation, pain and pyrexia in mammals.

The 2-(6'-methoxy-2'-naphthyl)-1-propyl 2"-acetoxybenzoate is prepared by esterifying 2-acetoxybenzoic acid with 2-(6'-methoXy-2'-naphthyl)-l-propanol. The 2"-carboxyphenyl 2-(6'-methoxy-2'-naphthyl)propionate is prepared by esterifying 2-(6'-methoxy-2'-naphthyl)propionic acid with salicylic acid. The preferred compounds are derived from I 2-(6'-methoxy-2-naphthyl)-1-propanol and d 2-(6-methoxy-2'-naphthyl)propionic acid, respectively with retention of the steric structure in the ester products.

The 2-(6-methoxy-2'-naphthyl)propionic acid and the respective d-isomer thereof together with methods for their preparation have been previously described in US. patent application Ser. No. 694,771, filed Dec. 7, 1967 and Ser. No. 741,858, filed July 2, 1968, both now abandoned. One such process comprises reacting the known 2- (6'methoxy-2-naphthyl)propanal with hydroxylamine hydrochloride to form the corresponding 2-(6'-methoxy-2' naphthyl)propionaldoxime which is converted to the corresponding 2-(6'-methoxy- -naphthyl)propionitrile by heating. Hydrolysis of the latter compound in an aqueous alkaline solution yields the corresponding 2-(6'-methoxy 2-naphthyl)propionic acid. The d-isomer is obtained by optical resolution of the latter compound such as by selective biological degradation or by preparation of diastereo isomer salts of the 2-(6-methoXy-2-naphthyl) propionic acid with a resolved optically active amine base such as cinchonidine and then separating the thus formed diastereo isomers by fractional crystallization. The separated diastereo isomer salts are then acid cleaved to yield the respective d 2-(6'-methoxy-2-naphthyl)propionic acid.

United States Patent ice The 2-(6'-methoxy-2'-naphthyl)-l-propanols and the corresponding l-isomers are prepared by reducing the corresponding 2-(6'-methoxy-2'-naphthyl)propionic acid and the d-isomer thereof with lithium aluminum hydride in an inert organic solvent such as an ether, e.g. tetrahydrofuran.

The compounds of this invention are especially useful in the treatment of inflammation, such as inflammatory conditions of the muscular skeletal system, skeletal joints and other tissues. Accordingly, these compounds are useful in the treatment of conditions characterized by inflammation, such as rheumatism, concussion, lacerations, arthritis, bone fractures, post-traumatic conditions and gout.

The preferred manner of administration is oral administration which provides the use of a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Generally, a daily dose of 1 mg. to 60 mg. of the active compound per kilogram of body weight of the mammal is employed. Most conditions respond to a treatment comprising a dosage level of from 2 mg. to 50 mg./kg. For oral administration, a pharmacuetically acceptable non-toxic composition can be formed by incorporating any of the normally employed excipients. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monosterate talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like. In addition, these compounds can be administered in conjunction with other medicinal agents selected for the specific condition being treated.

This invention is further illustrated by the following specific but nonlimiting examples.

EXAMPLE 1 To a solution of 2 ml. of trifluoroacetic anhydride in 10 ml. of benzene is added 1 g. of 2-acetoxybenzoic acid followed by 1 g. of 2-(6'-methoxy-2'-naphthyl)-1- propanol. After 1 hour at room temperature, the mixture is added to sodium bicarbonate solution. The benzene layer is separated, washed with water, and evaporated to dryness. The residue is recrystallized from acetone: hexane to yield 2-(6'-methoxy-2'-naphthyl)-1-propyl 2"- acetoxybenzoate.

Repeating the above procedure with l 2-(6'-methoxy- 2' naphthyl) l propanol yields 2-(6' methoxy 2'- naphthyl)-1-propyl 2"-acetoxybenzoate wherein the 2-(6'- methoxy-2'-naphthyl)-l-propy1 group has the isomeric structure of the starting compound.

EXAMPLE 2 To a solution of 2 ml. of trifluoroacetic anhydride in 10 ml. of benzene is added 1 g. of 2-(6'-methoxy-2'- naphthyDpropionic acid followed by 1 g. of salicylic acid. After one hour at room temperature, the benzene solution is washed with Water and evaporated to dryness. The residue is recrystallized from acetonezhexane to yield 2"-carboxyphenyl 2-(6'-methoxy-2'-naphthyl)propionate.

Repeating the above procedure with d 2-(6'-methoxy- 2'-naphthyl)propionic acid yields the corresponding ester of the d-isomer.

3 EXAMPLE 3 The following ingredients are mixed intimately and pressed into single scored tablets.

Quantity per tablet, mg.

Comp A B O D Ingredients:

2-(6'-methoxy-2'-naphthyl)-1-propy1 2"- aeetoxybenzoate 100 150 2-earboxyphenyl 2-(6-methoxy naphthyD-propionate 100 150 Cornstarch 200 200 100 100 Sucrose 40 4 T aotn a 400 Magnesium stearate 2 2 EXAMPLE 4 The following ingredients are mixed intimately and introduced into a hard-shell gelatin capsule.

Quantity P r capsule, mg.

Composition A B C D Ingredients:

2-(6-methoxy-2'-naphthy1)-1-propyl 2"- acetoxybenzo e- 100 100 '-eaxboxyphenyl2-(6-methoxy-2- naphthyD-propionate 100 100 Tantnen 190 190 200 200 Magnesium stearate 8 8 We claim:

1. A method for treating inflammation, pain or pyrexia comprising orally administering to a mammal an amount therapeutically effective to treat inflammation, pain or pyrexia, of a compound selected from the group consisting of 2 (6-methoxy-2'-naphthyl)-l-propyl 2"-acetoxybenzoate and 2"-carboxyphenyl 2-(6-methoxy-2'-naphthyl) propionate.

2. The method of claim 1 wherein the compound is 2"- carboxyphenyl 2- (6'-methoxy-2'-naphthyl)propionate.

3. A pharmaceutical composition for use in treating inflammation, pain or pyrexia in mammals comprising, in a dosage form suitable for oral administration, an amount therapeutically effective to treat inflammation, pain or pyrexia, of a compound selected from the group consisting of 2-(6'-methoxy-2-naphthyl)-1-propyl 2"-acetoxybenz0 ate and 2"-carboxyphenyl 2- (6'-methoXy-2'-naphthyl) propionate, and a pharmaceutically acceptable excipient.

4. The composition of claim 3 wherein the compound is 2"-carboxyphenyl 2-(6-metl1oxy-2'-naphthyl)propionate.

References Cited UNITED STATES PATENTS 3/1934 Wolfram 260108 OTHER REFERENCES JEROME D. GOLDBERG, Primary Examiner 

